FCARH143 / BMS, Fred Hutchinson Cancer Center, National Cancer Institute - LARVOL DELTA

A phase 1 trial of fully human BCMA CAR-T therapy for relapsed/refractory multiple myeloma with 5-year follow-up. (PubMed, Blood) - P1 | "FCARH143, an autologous BCMA-targeted CAR-T therapy which incorporates a fully human BCMA-specific scFv and 4-1BB costimulatory domain, was evaluated in a phase 1 trial (NCT03338972) for relapsed/refractory multiple myeloma (RRMM). FCARH143 demonstrated potent anti-myeloma activity with a 100% response rate and manageable toxicity, independent of disease burden or cytogenetic risk. Further evaluation in high-risk RRMM is warranted."

Journal • P1 data • Hematological Malignancies • Multiple Myeloma • Oncology

Gamma Secretase Inhibition May Mitigate the Impact of Low BCMA Target Density in Relapsed/Refractory Multiple Myeloma: Results from a Comparative Analysis of Two Phase 1 Clinical Trials (ASH 2024) - "Pts on FH9952 received the γ-secretase inhibitor (GSI), crenigacestat, during a pre-CAR-T run-in (3 doses 48 h apart) followed by post-infusion dosing 3x weekly for up to 9 doses. Limitations of this study include a small sample size and retrospective analysis. A randomized prospective study is needed to confirm a survival benefit of incorporating a GSI into treatment with FCARH143, or other BCMA CAR-T products."

Clinical • P1 data • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology

Single-cell analysis of the multiple myeloma microenvironment after gamma-secretase inhibition and CAR T-cell therapy. (PubMed, Blood) - "Leveraging a phase I clinical trial of the gamma-secretase inhibitor (GSI), crenigacestat, with anti-BCMA CAR T-cells (FCARH143), we utilized single-nuclei RNA sequencing and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to characterize the effects of GSI on the tumor microenvironment. Finally, we detected monoallelic deletion of the BCMA locus in some patients with prior exposure to anti-BCMA therapy, which significantly correlated with reduced progression-free survival (median PFS 57 days versus 861 days). GSIs are being explored in combination with the full spectrum of BCMA targeting agents, and our results reveal widespread effects of GSI on both tumor and immune cell populations, providing insight into mechanisms for enhancing BCMA-directed therapies."

CAR T-Cell Therapy • IO biomarker • Journal • Hematological Malignancies • Multiple Myeloma • Oncology

Impact of Gamma-Secretase Inhibition on the Multiple Myeloma Immune Microenvironment (ASH 2023) - "In a phase I, first-in-human clinical trial (n=18; relapsed/refractory MM) combining the GSI, crenigacestat, with anti-BCMA CAR T-cell therapy (FCARH143), we recently demonstrated that plasma cell BCMA antibody-binding capacity increased a median of 12-fold among 17/18 (94%) of participants after they received a 5-day GSI "run-in" (25 mg orally administered QOD for 3 doses) [Cowan AJ, et al...Accessibility of CD38, the target of daratumumab, was significantly increased in B cells, and SLAMF7, the target of elotuzumab, was significantly increased in plasma cells... BCMA cleavage from myeloma cells' surface is a putative resistance mechanism to BCMA-targeting immunotherapy. This study assessed the single-cell transcriptome and chromatin accessibility in the bone marrow environment of 16 patients given GSI monotherapy to ultimately enhance the efficacy of subsequent anti-BCMA CAR T-cell therapy. We found that prior BCMA-targeted therapy resulted in reduced..."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • ERBB4 • HES1 • Neurl1 • NOTCH1 • NOTCH2 • SLAMF7 • TNFRSF17

Immunotherapy With BCMA CAR-T Cells in Treating Patients With BCMA Positive Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=28 | Completed | Sponsor: Fred Hutchinson Cancer Center | Active, not recruiting ➔ Completed | Trial completion date: Dec 2037 ➔ Mar 2022

CAR T-Cell Therapy • Trial completion • Trial completion date • Hematological Malignancies • Multiple Myeloma • Oncology • SDC1